Attempts have been made recently to develop immunotherapies for the treatment of cancer based on stimulating the host immune response to the tumor. These approaches were based on attempts to immunize against specific tumor cells or with nonspecific stimulants in the hope that general immune stimulation would concomitantly increase the host antitumor response. Although some experimental evidence indicated that this approach might be feasible in the therapy of established tumors, the inability to stimulate sufficiently strong responses to putative tumor antigens and the general immunoincompetence of the tumor bearing host argued against the success of this approach.
An alternative therapeutic approach to the immunologic treatment of cancer is that of the adoptive transfer of immune cells. Adoptive immunotherapy is defined as the transfer to the tumor-bearing host of active immunologic reagents, such as cells with antitumor reactivity that can mediate, either directly or indirectly, antitumor effects. Adoptive immunotherapy represents an attractive approach to cancer therapy and to other conditions related to immune dysfunction. Because active immunologic reagents are transferred to the host, complete host immunocompetence is not required. Thus, the immunosuppression generally associated with the tumor bearing state does not represent a major problem when using this therapeutic alternative. Since host immunocompetence is not required, and in fact may be beneficial to the effects of the adoptive transfer of immune cells, adoptive immunotherapy can be easily combined with other therapies such as chemotherapy and radiation therapy. Since the transferred reagents are immunologically specific, this treatment modality predicts a high degree of specificity and consequently a low morbidity. Further, in contrast to most other therapies, no immunosuppression is likely to result from this treatment.
A review of previous attempts to perform adoptive immunotherapy for treatment of cancer in animals and humans can be found in Rosenberg et al.; 1977, Adv. Cancer Res. 25: 323-388.
Recent studies have demonstrated that the adoptive transfer of specifically immune or broadly cytotoxic lymphocytes generated in the presence of human recombinant interleukin-2 (rIL2) can result in the regression of established tumors in mice and humans. Similarly, the administration of rIL2 alone, in the absence of adoptive immunotherapy, also has been shown to produce some antitumor effects in mice and humans. However, the use of adoptive immunotherapy and rIL2 to treat cancer patients is a complicated, expensive, and toxic form of therapy.
The disadvantage of the use of large amounts of rIL2 either by itself or in combination with adoptive immunotherapy is that such treatment induces a variety of severe and dose-limiting toxic side effects. Therefore, much attention has recently focused on alternative strategies that could exploit the therapeutic benefits of IL-2 while decreasing the expense and logistic difficulties associated with adoptive immunotherapy, as well as decreasing the toxic sequelae associated with high-dose IL-2 therapy.
Renca murine renal cancer has successfully been treated by a therapeutic regimen which combines doxorubin hydrochloride (DOX) and adoptive immunotherapy (AIT) with IL-2, as described in Salup et al., J. Immunol., 138: 641 (1987), and Salup et al., Cancer Res., 46: 3358 (1986). This approach has the advantage of requiring daily administration of a moderate amount of IL-2 rather than the larger amounts required to demonstrate therapeutic effects with IL-2 alone.
Compounds of the formula ##STR1## in which AR is phenyl substituted by lower alkyl or lower alkoxy, or AR is thienyl, or furyl; R.sub.1 is hydrogen; B is a lower linear or branched alkylene or alkenylene radical; X is hydrogen, lower alkyl or lower alkoxy; n equals 1; R.sub.2 is hydrogen a lower dialkylamino lower alkyl or morpholinoethyl; or an alkali metal salt of said acid, have been disclosed in U.S. Pat. No. 4,602,234, which is incorporated herein by reference, and in French Patent No. 2,536,397. At the 18th International Leucocyte Culture Conference of June 1987, it was disclosed that the antitumor activity of flavone-8-acetic acid (FAA), a compound disclosed in that patent, was enhanced by administration with interleukin-2.